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Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

Publication ,  Journal Article
Dewey, FE; Gusarova, V; Dunbar, RL; O'Dushlaine, C; Schurmann, C; Gottesman, O; McCarthy, S; Van Hout, CV; Bruse, S; Dansky, HM; Leader, JB ...
Published in: N Engl J Med
July 20, 2017

BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

July 20, 2017

Volume

377

Issue

3

Start / End Page

211 / 221

Location

United States

Related Subject Headings

  • Mutation
  • Middle Aged
  • Mice, Inbred Strains
  • Mice
  • Male
  • Lipids
  • Lipid Metabolism
  • Humans
  • General & Internal Medicine
  • Female
 

Citation

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Dewey, F. E., Gusarova, V., Dunbar, R. L., O’Dushlaine, C., Schurmann, C., Gottesman, O., … Baras, A. (2017). Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med, 377(3), 211–221. https://doi.org/10.1056/NEJMoa1612790
Dewey, Frederick E., Viktoria Gusarova, Richard L. Dunbar, Colm O’Dushlaine, Claudia Schurmann, Omri Gottesman, Shane McCarthy, et al. “Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.N Engl J Med 377, no. 3 (July 20, 2017): 211–21. https://doi.org/10.1056/NEJMoa1612790.
Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 Jul 20;377(3):211–21.
Dewey, Frederick E., et al. “Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.N Engl J Med, vol. 377, no. 3, July 2017, pp. 211–21. Pubmed, doi:10.1056/NEJMoa1612790.
Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, McCarthy S, Van Hout CV, Bruse S, Dansky HM, Leader JB, Murray MF, Ritchie MD, Kirchner HL, Habegger L, Lopez A, Penn J, Zhao A, Shao W, Stahl N, Murphy AJ, Hamon S, Bouzelmat A, Zhang R, Shumel B, Pordy R, Gipe D, Herman GA, Sheu WHH, Lee I-T, Liang K-W, Guo X, Rotter JI, Chen Y-DI, Kraus WE, Shah SH, Damrauer S, Small A, Rader DJ, Wulff AB, Nordestgaard BG, Tybjærg-Hansen A, van den Hoek AM, Princen HMG, Ledbetter DH, Carey DJ, Overton JD, Reid JG, Sasiela WJ, Banerjee P, Shuldiner AR, Borecki IB, Teslovich TM, Yancopoulos GD, Mellis SJ, Gromada J, Baras A. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 Jul 20;377(3):211–221.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

July 20, 2017

Volume

377

Issue

3

Start / End Page

211 / 221

Location

United States

Related Subject Headings

  • Mutation
  • Middle Aged
  • Mice, Inbred Strains
  • Mice
  • Male
  • Lipids
  • Lipid Metabolism
  • Humans
  • General & Internal Medicine
  • Female